CCR2-dependent monocyte-derived cells restrict SARS-CoV-2 infection

SARS-CoV-2 has caused a historic pandemic of respiratory disease (COVID-19) and current evidence suggests severe disease is associated with dysregulated immunity within the respiratory tract1,2. However, the innate immune mechanisms that mediate protection during COVID-19 are not well defined. Here we characterize a mouse model of SARS-CoV-2 infection and find that early CCR2-dependent infiltration of monocytes restricts viral burden in the lung. We find that a recently developed mouse-adapted MA-SARS-CoV-2 strain, as well as the emerging B.1.351 variant, trigger an inflammatory response in the lung characterized by expression of pro-inflammatory cytokines and interferon-stimulated genes. Using intravital antibody labeling, we demonstrate that MA-SARS-CoV-2 infection leads to increases in circulating monocytes and an influx of CD45+ cells into the lung parenchyma that is dominated by monocyte-derived cells. scRNA-seq analysis of lung homogenates identified a hyper-inflammatory monocyte profile. We utilize this model to demonstrate that mechanistically, CCR2 signaling promotes infiltration of classical monocytes into the lung and expansion of monocyte-derived cells. Parenchymal monocyte-derived cells appear to play a protective role against MA-SARS-CoV-2, as mice lacking CCR2 showed higher viral loads in the lungs, increased lung viral dissemination, and elevated inflammatory cytokine responses. These studies have identified a CCR2-monocyte axis that is critical for promoting viral control and restricting inflammation within the respiratory tract during SARS-CoV-2 infection. 8 samples in total corresponding to different mice. 4 samples are from mock, control mice. 4 samples are from SARS-CoV-2 infected mice.

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引发了具有历史意义的呼吸道疾病（COVID-19）大流行，现有研究证据表明，重症疾病与呼吸道内的免疫失调密切相关^1,2。然而，介导COVID-19防护效应的先天免疫机制尚未得到明确阐明。本研究对一种SARS-CoV-2感染小鼠模型进行了表征，发现早期CCR2依赖的单核细胞浸润可限制肺部的病毒负荷。研究发现，新近开发的小鼠适应型MA-SARS-CoV-2毒株以及新兴的B.1.351变异株，均可触发肺部炎症反应，其特征为促炎细胞因子与干扰素刺激基因的表达上调。通过活体抗体标记实验，本研究证实MA-SARS-CoV-2感染会导致循环单核细胞增多，并使CD45阳性细胞涌入肺实质，其中以单核细胞衍生细胞为主。对肺组织匀浆进行的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）分析鉴定出了一种高炎症性单核细胞表型。利用该模型，本研究从机制层面证实CCR2信号通路可促进经典单核细胞向肺部浸润，并扩增单核细胞衍生细胞群体。肺实质内的单核细胞衍生细胞似乎对MA-SARS-CoV-2具有防护作用：缺失CCR2的小鼠肺部病毒负荷更高、肺部病毒播散更为严重，且促炎细胞因子反应增强。本研究明确了一条CCR2-单核细胞轴，该轴在SARS-CoV-2感染期间对于促进病毒控制、限制呼吸道内炎症反应至关重要。本数据集共包含8个样本，均来自不同小鼠：其中4个样本取自空白对照（mock）小鼠，剩余4个样本取自SARS-CoV-2感染小鼠。